Clinical gene transfer with adeno-associated viral (AAV) vectors has rapidly gained momentum in recent years. The ongoing translation from bench-to-bedside has been spurred in part by the availability of a versatile AAV toolkit displaying diverse tissue tropisms across multiple species [1,2]. Amongst numerous AAV isolates, AAV9 vectors display a systemic, multi-organ transduction profile following intravenous administration [3]. Rapid onset of gene expression and high transgene expression levels mediated by AAV9 vectors in heart and liver have been reported [4,5,6]. In addition, efficient transduction of neurons in neonatal mice as well as skeletal muscle in neonatal dogs following intravascular administration has been observed [7, 8]. These attributes make AAV9 a viable candidate for therapeutic gene transfer in systemic diseases such as lysosomal storage disorders.
Paradoxically, a wide range of clinically relevant applications benefit from vector targeting to specific tissues rather than multi-organ gene expression. For instance, gene therapy of cardiac disease or muscular dystrophies would be facilitated by vectors capable of efficient and selective gene transfer to heart and/or skeletal muscle [6,8,9]. Therapeutic approaches targeting the liver or skeletal muscle are preferred for treatment of hemophilic disorders [10], while the lung is considered a target organ for gene therapy of alpha-1 antitrypsin (AAT) deficiency [11,12].
The present inventor addresses a need in the art for nucleic acid delivery vectors with desirable features, e.g., with respect to transduction profiles.